1. Field of the Invention Present invention generally relates to drug formulation. In particular it relates to an oral formulation of tetrapyrrole compounds and their derivatives, to be used in the photodynamic therapy (PDT), Antimicrobial Photodynamic therapy (APDT) and even for photodiagnosis purpose. This formulation will be administered orally.
2. Invention Disclosure Statement
Photosensitizers are compounds which can be photoactivated by irradiation of specific wavelength matching the absorption spectrum of the photosensitizer. Photosensitizers are used in Photodynamic Therapy (PDT) treatment, a novel method used initial in treating cancer and now found to be effective in treating other medical problems also. PDT method is used to treat different kinds of cancers including proliferating and non-proliferating types, Benign Prostate Hyperplasia (BPH), other Inflammatory conditions, cosmetic applications and others. Generally photosensitizers are administered to patient systemically and topically, which both have their own merits and demerits.
In general, photosensitizers are now delivered topically or intravenously. Especially, the intravenous delivery poses problems for the medical treatment as many photosensitizers are hydrophobic or amphiphilic substances which are non-soluble in water. Sometimes the photosensitizers are administered in alcoholic solution (ethanol, propylene glycol) as e.g. the photosensitizer temoporfin. However, the alcohol content can induce pain during administration and alcohol as a solubilizing agent in general is not feasible for certain groups of patients. Therefore, there have been efforts to formulate hydrophobic photosensitizers in a way that renders them water-soluble. These approaches include many different carrier systems such as liposomes, nanoparticles, quantum dots, or carrier systems based on inorganic materials. Of special interest in this respect are carrier systems based on highly biocompatible materials such as lipids, proteins or biocompatible polymers. There are a number of such carrier systems known in the art (F. L. Primo, P. P. Macaroff, Z. G. M. Lacava, R. B. Azevedo, P. C. Marais, A. C. Tedesco, Binding and photophysical studies of biocompatible magnetic fluid in biological medium and development of magnetic nanoemulsion: A new candidate for cancer treatment. J. Magnetism Magn. Mater., 2007, 310, 2838-2840; patent application WO 06133271A2; A. J. Gomes, C. N. Lunardi, A. C. Tedesco, Characterization of biodegradable poly(D,L-lactide-co-glycolide) nanoparticles loaded with bacteriochlorophyll-a for photodynamic therapy, Photomed. Laser Surg., 2007, 25, 428-435; E. Ricci-Junior, J. M. Marchetti, Preparation, characterization, photocytotoxicity assay of PLGA nanoparticles containing zinc(II) phthalocyanine for photodynamic therapy use, J. Microencapsul., 2006, 23, 523-538; E. Ricci-Junior, J. M. Marchetti, Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use, Int. J. Pharm., 2006, 310, 187-195; V. Saxena, M. Sadoqi, J. Shao, Polymeric nanoparticulate delivery system for indocyanine green: Biodistribution in healthy mice, Int. J. Pharm., 2006, 308, 200-204; A. Vargas, B. Pegaz, E. Debefve, Y. Konan-Kouakou, N. Lange, J.-P. Ballini, H. van den Bergh, R. Gurny, F. Delie, Improved photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using chick embryos, Int. J. Pharm., 2004, 286, 131-145; Y. N. Konan, M. Berton, R. Gurny, E. Allémann, Enhanced photodynamic activity of meso-tetra(4-hydroxyphenyl)porphyrin by incorporation into sub-200 nm nanoparticles, Eur. J. Pharm. Sci., 2003, 18, 241-249; Y. N. Konan, R. Cerny, J. Favet, M. Berton, R. Gurny, E. Allémann, Preparation and characterization of sterile sub-200 nm meso-tetra(4-hydroxyphenyl)porphyrin loaded nanoparticles for photodynamic therapy, Eur. J. Pharm. Biopharm., 2003, 55, 115-124; A. Vargas, M. Eid, M. Fanchaouy, R. Gurny, F. Delie, In vivo photodynamic activity of photosensitizer-loaded nanoparticles: Formulation properties, administration parameters and biological issues involved in PDT outcome, Eur. J. Pharm. Biopharm., 2008, 69, 43-53; B. Pegaz, E. Debefve, F. Borle, J.-P. Ballini, H. Van den Bergh, Y. N. Kouakou-Konan, Encapsulation of porphyrins and chlorins in biodegradable nanoparticles: The effect of dye lipophilicity on the extravasation and the photothrombic activity. A comparative study, J. Photochem. Photobiol. B: Biology, 2005, 80, 19-27; patent application WO 97010811A1 and patent application WO 03097096A1). However, these water-soluble carrier systems were developed for intravenous administration. They have not yet been evaluated for their potential for oral administration.
Oral administration is one of the easiest routes for drug administration and is particularity useful for patient compliance. The main hurdles faced in oral administration of drugs include biological barriers which makes it difficult for poorly water soluble drug molecules to be administered orally. Commonly the drug size, its bioavailability, the solubility and stability makes it difficult to pass through the biological barriers like the intestinal mucosa and gut epithelium. To overcome these biological barriers drug development and manufacturing units have found novel methods of formulation using more efficient delivery systems. Newer drug delivery systems are formulated to avoid the drug being accumulated in non-targeted site such as spleen and liver thus increasing dramatically the drug half life in the circulatory system. This is difficult in some cases, as well as undesirable if it is the liver for example which contains cancerous tissue.
Oral drug delivery system development has been fostered by the need to deliver medications to patients more efficiently and with fewer side effects. The oral route is found to be the most convenient route of drug administration. The oral and other therapeutic systems in human use have been validated as concepts for controlled continuous drug release which can minimize the daily dose or the number of doses of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. Oral drug delivery systems in particular have required innovation in material science to provide biocompatible materials during prolonged contact with body tissues, bioengineering methods to develop drug delivery modules, and clinical pharmacology studies for elucidation of drug pharmacokinetics under conditions of continuous controlled drug administration.
Oral drug delivery systems/methods provide the possibility to maintain therapeutically optimum drug concentrations in plasma and target organs; and therefor eliminate the need for frequent single dose administration. Many pharmaceutical active agents used as medicines and supplements need to be stabilized and protected against degradation or oxidation activity using suitable carrier systems. The effectiveness of such agents may be improved by increasing their solubility in body fluids or by masking their unwanted properties (such as toxicity, odor, taste and other characteristics) before reaching the target organ using drug delivery systems.
Oral administration of unstable, insoluble and bad tasting active agents would require a delivery system which can stabilize the drug, avoid precipitation, and prevent early degradation. It also calls for a system which can improve the solubility. A system to mask the bad taste, reduce toxicity and side effects. Drug formulation units use different means to achieve these characteristics by using carrier system like nano-capsule, microspheres, liposomes, and pegylation. These carrier systems are made of biocompatible polymers, lipids or even natural/synthetic proteins. Natural stable proteins/lipids have been used because of their less immunogenic properties, and additionally can be used for specific targeting.
Drug delivery systems have been widely used to administer drugs with high molecular weight, having low solubility and permeability and having high susceptibility to enzymatic action in the GIT. Examples of macromolecules include peptides, proteins, nucleotides, sugars, etc. In prior art we see many such examples of using drug delivery systems for oral administration.
In U.S. Pat. No. 7,432,369 by Williams et al., discloses pyridyl-substituted Porphyrin compounds and their effective amount used in treating various disorders. They also discuss the method of administrating the drug which include oral route along with other well established methods. Composition for oral administration of their invention include tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. The method of formulating the oral formulation is not discussed.
Prasad, et al., in their U.S. Pat. No. 7,364,754 disclose a certain ceramic based nanoparticle agents for encapsulating hydrophobic photosensitizers used in PDT methods. Such nanoparticles entrapping drug/dyes can be administrated orally, parenterally or topically. The specific photosensitizer used here is 2-devinyl-2-(1-hexyloxyethyl)pyropheophorbide.
Robinson in his U.S. Pat. No. 6,376,483 discloses use of bacteriochlorins and bacteriopurpurins and their production methods. In his disclosure he describes the oral administration of this active agents using inert diluent or with assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets or incorporated directly in food. This patent basically describes new routes for synthesis of bacteriochlorins and bacteriopurpurins from symmetrical and asymmetrical mesodiacrylate porphyrins and their uses in PDT treatment.
In U.S. Patent Application No. 2007/0237827 by Sung et al., disclose a oral formulation consisting of biodegradable nanoparticles encapsulating therapeutically active agents like HMG-CoA reductase inhibitors, erythropoietin etc., to be orally delivered showing effective paracellular permeability. This patent does not discuss photosensitizer, but relates to nanoparticles as carrier for hydrophilic protein having high molecular weight which cannot easily be absorbed in the gut and also to prevent the proteases activity on the enclosed proteineous drug.
Harel in his U.S. patent Application No. 2008/044481 discloses use of microparticles for oral administration of bioactive agents like drug, protein, vitamins, probiotic organism etc. The encapsulation material can be made of oil, polysaccharides, proteins, synthetic polymers or combination of these.
In publication WO 2007/122613, by Yoav D. Livney et al., the inventors describe a method of encapsulating hydrophobic compounds including nutrients, therapeutic and cosmetic compounds and their administration via food and beverages. Especially used milk protein casein for the encapsulation.
Generally photosensitizers in the prior art are administrated systemically or topically, depending on the place of treatment and drug properties. The solubility, molecular size and stability are certain factors used to decide the mode of administration. The present invention provides a oral formulation which can be easily administered to the patient through the oral route without any complication such as pain due to needle pricks, or staining of skin due to local application etc. Present invention aims to provide a formulation which can be easily absorbed by the gastrointestinal tract.